RESUMO
T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive leukemia with inferior prognosis. Although activating mutations of NOTCH1 are observed in most T-ALL cases, these mutations alone are not sufficient to drive the full development of T-ALL. ß-Arrestins (ARRB) are versatile and multifunctional adapter proteins that regulate diverse cellular functions, including promoting the development of cancer. However, the role of ARRBs in T-ALL has largely remained elusive. In this study, we showed that ARRB1 is expressed at low levels in assayed T-ALL clinical samples and cell lines. Exogenous ARRB1 expression inhibited T-ALL proliferation and improved the survival of T-ALL xenograft animals. ARRB1 facilitated NOTCH1 ubiquitination and degradation through interactions with NOTCH1 and DTX1. Mechanistically, the oncogenic miRNA (oncomiR) miR-223 targets the 3'-UTR of ARRB1 (BUTR) and inhibits its expression in T-ALL. Furthermore, overexpression of the ARRB1-derived miR-223 sponge suppressed T-ALL cell proliferation and induced apoptosis. Collectively, these results demonstrate that ARRB1 acts as a tumor suppressor in T-ALL by promoting NOTCH1 degradation, which is inhibited by elevated miR-223, suggesting that ARRB1 may serve as a valid drug target in the development of novel T-ALL therapeutics.Significance: These findings highlight a novel tumor suppressive function of the adaptor protein ß-arrestin1 in T-ALL.
Assuntos
MicroRNAs/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/metabolismo , Proteínas Supressoras de Tumor/genética , beta-Arrestina 1/genética , Regiões 3' não Traduzidas/genética , Adolescente , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Criança , Pré-Escolar , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Masculino , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Proteólise , RNA-Seq , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Arrestina 1/metabolismoRESUMO
OBJECTIVE: To explore the correlation of EB virus infection with the prognosis of B-ALL children. METHODS: The peripheral blood of children with newly diagnosed B-ALL admitted in Children's Hospital of Chongqing Medical University from January 2012 to December 2017 were collected, and the EBV DNA in plasma was detected by real-time quantitative PCR. The clinical data of B-ALL children were collected and the correlation of EBV infection with the prognosis of B-ALL children was analyzed. RESULTS: Among 162 B-ALL children, the EBV infection rate was 41.36%. Univariate analysis showed that the B-ALL children with EBV infection had the poor prognosis and higher risk of shorter survival time, as compared with B-ALL children without EBV infection (HR=2.373, 95% CI: 1.129-4.987) (Pï¼0.05), the multivariate analysis showed that the result was consistent with result of univariate analysis indicating that EBV infection was an independent predictor for poor prognosis of B-ALL children. CONCLUSION: The EBV infection may play an important role in the occurrence and progression of B-ALL and is an independent predictor for poor prognosis, therefore the detection of EBV DNA in plasma of B-ALL children possesses an important significance for evaluation of B-ALL children's prognosis.